Arylation of Terminal Alkynes by Aryl Iodides Catalyzed by a Parts-per-Million Loading of Palladium Acetate

Article abstract of DOI:10.1021/acscatal.9b04593

Arylation of terminal alkynes (16 varieties) by aryl iodides (28 varieties) was achieved with a mol ppm loading level of palladium catalyst, where a variety of functional groups including heteroarenes were tolerated. Thus, the arylations were carried out in the presence of palladium acetate at ppm loadings and potassium carbonate in ethanol at 80 °C to give the corresponding internal alkynes in good to excellent yields. Synthesis of 2-phenyl-3-(phenylalkynyl)benzofuran was achieved by iterative use of the alkyne arylation under mol ppm catalytic conditions. Reaction-rate analysis, transmission electron microscopic (TEM) examination of the reaction mixture, and mercury-amalgamation test were performed to gain insight into the active species of the highly active ppm catalytic species. TEM examination of the reaction mixture revealed that palladium nanoparticles were generated in situ under the reaction conditions, and their cluster size was variable during the catalytic reaction. A variation in size of palladium particles suggested that the composition-decomposition process of Pd aggregates should take place in situ via monomeric palladium(0) species and/or fine palladium(0) clusters, which might be real catalytic species in this reaction.

Full text of DOI:10.1021/acscatal.9b04593

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Article
Arylation of Terminal Alkynes by Aryl Iodides Catalyzed
by a Parts per Million Loading of Palladium Acetate
Go Hamasaka, David Roy, Aya Tazawa, and Yasuhiro Uozumi
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04593 • Publication Date (Web): 08 Nov 2019
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Page 1 of 18
ACS Catalysis
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Arylation of Terminal Alkynes by Aryl Iodides Catalyzed by a Parts per Million Loading of
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Palladium Acetate
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Go Hamasaka,† David Roy,† Aya Tazawa,† Yasuhiro Uozumi*†‡
† Institute for Molecular Science (IMS), Myodaiji, Okazaki 444-8787, Japan
‡ JST-ACCEL, Myodaiji, Okazaki 444-8787, Japan
ABSTRACT: Arylation of terminal alkynes (16 varieties) by aryl iodides (28 varieties) was achieved with a mol ppm loading level of
palladium catalyst, where a variety of functional groups including heteroarenes were tolerated. Thus, the arylations were carried
out in the presence of palladium acetate at ppm loadings and potassium carbonate in ethanol at 80 ºC to give the corresponding
internal alkynes in good to excellent yields. Synthesis of 2-phenyl-3-(phenylalkynyl)benzofuran was achieved by iterative use of the
alkyne arylation under mol ppm catalytic conditions. Reaction-rate analysis, transmission electron microscopic examination of the
reaction mixture, and mercury-amalgamation test were performed to gain insight into the active species of the highly active ppm
catalytic species. Transmission electron microscopic (TEM) examination of the reaction mixture revealed that palladium
nanoparticles were generated in situ under the reaction conditions, and their cluster size was variable during the catalytic reaction.
A variation in size of palladium particles suggested that the composition-decomposition process of Pd aggregates should take place
in situ via monomeric palladium(0) species and/or fine palladium(0) clusters which might be real catalytic species in this reaction.
KEYWORDS: Arylation, Alkynes, Aryl Iodides, Palladium, Parts per Million
INTRODUCTION
a mole percent loading of the catalyst is still required to obtain
the desired internal alkynes efficiently within reasonable
reaction times. Although several research groups have
investigated the arylation of terminal alkynes in the presence
of part per million loadings of palladium catalysts, the catalytic
systems were generally complicated and involved, for
example, special palladium catalysts, bases, or solvents.14
Furthermore, the substrate scope in the presence of parts per
million loadings of palladium catalysts remains limited. The
reaction would therefore be more useful if it could be
promoted by a parts per million loading of a simple palladium
catalyst and if it could be applied to a variety of the substrates
under mild conditions. Very recently, highly efficient ppm
palladium-catalyzed copper-free Sonogashira coupling was
developed by Handa and Lipsutz.15-17 Clearly, while pioneering
strides have been made, additional studies on ppm palladium
protocols using a highly accessible palladium source are
warranted. In this report, we describe the arylation of various
terminal alkynes with aryl iodides containing diverse functional
groups in the presence of a parts per million loading of
Pd(OAc)2 and K2CO3 in ethanol to give the corresponding
internal alkynes in good to excellent yields (52 examples). We
also examined the nature of the catalytically active species in
this system by using reaction-rate analysis, transmission
Palladium-catalyzed cross-coupling reactions are recognized as
useful and important methods for synthesizing a variety of
pharmaceuticals, agrochemicals, organic functional materials,
etc.1 However, these reactions often require mole percent
levels of palladium species, based on the starting materials, to
obtain the target compounds efficiently, resulting in potential
contamination of the products by metallic residues. These
palladium contaminants have to be removed from the
products, because transition metals tend to be toxic toward
living species and can impair the performance of organic
functional materials.2,3 In addition, some transition-metal
species are limited resources on this planet and must be
conserved to achieve sustainable development. Decreasing
the catalyst loading provides a simple and straightforward
solution to these difficulties. Consequently, organic chemists
have attempted to develop highly efficient catalytic systems.4–6
In this context, we also have developed efficient catalytic
systems based on a palladium NNC-pincer complex for
arylation of allyl esters and alkenes.7,8
The palladium-catalyzed arylation of terminal alkynes is a
method commonly used for the synthesis of internal alkynes.
Pioneering works on this reaction were independently
reported in 1975 by Dieck and Heck,9 Cassar,10 and Sonogashira
and co-workers.11 Among these reactions, the Sonogashira
reaction, in which a catalytic quantity of a copper salt and a
stoichiometric amount of an amine as a base are used,
proceeds efficiently under mild conditions with a broad
tolerance of functional groups. Further studies on this protocol
for the arylation of terminal alkynes have shown that the
reaction proceeds in the absence of a copper salt;12,13 however,
electron microscopic measurements, and
amalgamation experiment.
a mercury-
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RESULTS AND DISCUSSION
Table 1. Screening of Conditions for the Reaction of 4-
Iodotoluene (1a) with Ethynylbenzene (2A)a
1
2
3
4
5
6
7
8
Initially, we screened the conditions for the coupling of 4-
iodotoluene (1a) with ethynylbenzene (2A) (Table 1). The
reaction was carried out in the presence of 5 mol ppm
palladium acetate and 1.5 equivalents of potassium carbonate
in a variety of solvents. The reaction did not proceed at all in
water or methanol (Table 1, entries 1 and 2) but it proceeded
cat (5.0 mol ppm Pd)
+
I
base (2.0 equiv)
solvent, 80 ºC, 24 h
1a
3aA
2A
(1.5 equiv)
Yieldb
(%)
0
Entry Catalyst
Base
Solvent
efficiently
in
ethanol
to
give
1-methyl-4-(2-
phenylethynyl)benzene (3aA) in 95% yield (entry 3). When
propan-1-ol, isopropyl alcohol, or butan-1-ol was used as the
solvent, 3aA was obtained in yields of 50, 30, and 52%,
respectively (entries 4–6). Ethylene glycol, 1,4-dioxane, and
tetrahydrofuran were not suitable solvents for this reaction
(entries 7–9). These results therefore showed that ethanol is
the best solvent in this reaction. We next tested a variety of
bases. However, the reaction did not proceed efficiently in the
presence of other inorganic or organic bases [sodium
carbonate, cesium carbonate, potassium acetate, potassium
phosphate, potassium fluoride, sodium hydroxide,
triethylamine, piperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), or 1,4-diazabicyclo[2.2.2]octane (DABCO)] (entries 10–
19). We also optimized the amount of potassium carbonate
(entries 20 and 21) and found that three equivalents were
optimal for this reaction. The loading of palladium acetate
could be decreased to 2.3 mol ppm (entry 22). Screening of the
palladium catalyst was also performed. The use of
9
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
H2O
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MeOH
EtOH
PrOH
iPrOH
BuOH
0
95
50
30
52
ethylene
glycol
7
Pd(OAc)2
K2CO3
0
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3
K2CO3
Na2CO3
Cs2CO3
KOAc
K3PO4
KF
1,4-dioxane
THF
0
9
0
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22
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27
EtOH
17
0
EtOH
EtOH
0
EtOH
0
tetrakis(triphenylphosphine)palladium,
palladium–allyl
EtOH
0
chloride, palladium chloride, or palladium nitrite gave 3aA in
yields of 72, 75, 58, and 45%, respectively (entries 23–26).
Palladium acetate was therefore the most effective catalyst
among the palladium catalysts studied. The reaction did not
proceed at all in the absence of a palladium catalyst (entry 27).
The use of anhydrous ethanol as the solvent led to an increase
in the yield of 3aA (entry 28). A further decrease in the catalyst
loading to 1.0 mol ppm gave the lower yield of 3aA (entry 29).
We also examined the transmission electron microscopic
(TEM) analysis of the reaction mixtures of selected entries
(Figure 1). While big size clusters of palladium ( = ca. 10-18)
were observed in the reaction mixtures using H2O and THF
(Figure 1a and 1c) which showed little catalytic activity for the
coupling reaction, fine nanoparticles of palladium having ca.
2.1 nm of average diameter were generated in situ in EtOH in
the presence of K2CO3 at 80 °C (Figure 1b) to promote the
reaction efficiently (see also Table 1, entries 1, 3, and 9). In
contrast, use of Et3N in EtOH gave catalytically inactive giant
clusters during the reaction as shown in Figure 1d. Thus,
EtOH/K2CO3 were essential to generate highly catalytically
active fine nanoparticles under the reaction conditions.
NaOH
Et3N
EtOH
0
EtOH
0
piperidine EtOH
0
DBU
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
0
DABCO
24
93
100
91
72
75
45
58
0
c
K2CO3
d
K2CO3
e
d
K2CO3
e
d
Pd(PPh3)4
K2CO3
e
d
[PdCl(C3H5)]2
K2CO3
e
d
Pd(NO3)2
K2CO3
e
d
PdCl2
K2CO3
d
none
K2CO3
100
e
d
28f
29f
Pd(OAc)2
K2CO3
EtOHg
EtOHg
(93)h
i
d
Pd(OAc)2
K2CO3
21
a
Reaction conditions: 1a (0.5 mmol), 2A (0.75 mmol), catalyst
(2.5 × 10−6 mmol), base (1.0 mmol), solvent (2 mL), 80 °C, 24 h.
b
NMR yield. c K2CO3 (1.5 equiv, 0.75 mmol). d K2CO3 (3.0 equiv, 1.5
mmol). e Catalyst (2.3 mol ppm). 2A (1.1 equiv, 0.55 mmol).
f
g
Anhyd EtOH. h Isolated yield. i Catalyst (1 mol ppm).
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ACS Catalysis
5 mol ppm palladium acetate to afford the desired internal
1
2
3
4
5
6
7
8
alkyne 3mC in 97% yield. In the reactions of 2-
ethynylthiophene (2D) or 3-ethynylpyridine (2E), 50 mol ppm
of palladium acetate was required to promote the reaction and
the yields of the desired products 3mD and 3mE were
relatively low (49 and 25%, respectively). 1-
Ethynylcyclohexene (3F) reacted to give 1-chloro-4-(cyclohex-
1-en-1-ylethynyl)benzene (3mF) in 99% yield. The reaction
with a silylated acetylene, tert-butyl(ethynyl)dimethylsilane
(2G), gave the silylated ethynylbenzene 3mG in 51% yield. Our
catalytic system could also be used in the reactions of aliphatic
alkynes. The reaction of 1m with 3,3-dimethylbut-1-yne (2H)
or dec-1-yne (2I) in the presence of 20 or 50 mol ppm of
palladium acetate, respectively, gave the corresponding
coupling products 3mH and 3mI in yields of 73 and 94% yields,
respectively. The hydroxylated cyclic and linear aliphatic
terminal alkynes 2J and 2K similarly gave the desired internal
alkynes 3mJ and 3mK in yields of 81 and 50%, respectively.
(a)
(b)
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In H2O with K2CO3 (Table 1, entry 1)
Average diameter = ca. 9.8 nm.
In EtOH with K2CO3 (Table 1, entry 3)
Average diameter = ca. 2.1 nm.
(c)
(d)
Scheme 1. Substrate Scope in the Reaction of Iodobenzenes 1
with Terminal Alkynes 2a
Pd(OAc)2 (x mol ppm)
I
R2
R2
+
R1
R1
K2CO3 (3 equiv)
EtOH, 80 ˚C, 24 h
2 (1.1 equiv)
1
3
R
R
In THF with K2CO3 (Table 1, entry 9)
Average diameter = ca. 18 nm.
In EtOH with Et3N (Table 1, entry 16)
Average diameter = ca. 46 nm.
R
3vA R = Me, 99% (x = 2.3)
3wA R = OMe, 71% (x = 10)
3xA R = i-Pr, 91% (x = 10)
3yA R = Ph, 72% (x = 10)
3zA R = F, 88% (x = 5)
Figure 1. TEM images for the reaction of 1a and 2A under
3aA R = Me, 93% (x = 2.3)
3bA R = H, 97% (x = 2.3)
3cA R = OMe, 99% (x = 10)
3dA R = t-Bu, 98% (x = 5)
3eA R = Ph, 88% (x = 5)
3fA R = CF3, 97% (x = 2.3)
3gA R = COMe, 88% (x = 2.3)
3hA R = CO2Et, 46% (x = 5)
3iA R = CN, 76% (x = 5)
3jA R = NO2, 84% (x = 10)
3kA R = CH2OH, 90% (x = 5)
3lA R = F, 90% (x = 5)
3oA R = Me, 99% (x = 2.3)
3pA R = OMe, 88% (x = 10)
3qA R = CF3, 99% (x = 2.3)
3rA R = NO2, 90% (x = 10)
3sA R = COMe, 73% (x = 5)
3tA R = Cl, 99% (x = 2.3)
3uA R = Br, 70% (x = 10)
the conditions shown in Table 1.
3aaA R = Cl, 99% (x = 10)
3abA R = Br, 63% (x = 5)
Having optimized the reaction conditions, we next examined
the substrate scope of this reaction (Scheme 1). The reaction
of ethynylbenzene (2a) with iodobenzene substrates 1 with
various para-substituents, including electron-donating or -
withdrawing groups, in the presence of 2.3–10 mol ppm
palladium acetate gave the corresponding diphenylalkynes
3aA–3nA in isolated yields of 46–99%. With our catalytic
system, meta- and ortho-substituted iodobenzenes 1o–1ab
also participated in the reaction to give the desired
diphenylalkynes 3oA–3abA in isolated yields of 70–99%.
Fluoro (1l and 1z), chloro (1m, 1t, 1aa, and 1ae), and bromo
(1n, 1u, and 1ab) groups remained intact after the reaction.18
Sterically hindered 2,6-disubstituted iodobenzenes 1ac and
1ad reacted with 2A to afford the corresponding
diphenylalkynes 3acA and 3adA in yields of 71 and 45%,
respectively. Our catalytic system could also be applied to the
reactions of 3,5-bis(trifluoromethyl)iodobenzene (1af), 2-
iodonaphthalene (1ag), and 9-iodophenanthrene (1ah).
Iodinated N-heteroaromatics 1ai and 1aj also underwent the
reaction in the presence of a mol ppm loading of palladium
acetate to give the corresponding internal alkynes 3aiA and
3ajE in yields of 99 and 52%, respectively.
OMe
OMe
3mA R = Cl, 92% (x = 2.3)
3nA R = Br, 61% (x = 5)
3acA 71% (x = 10)
3adA 45% (x = 10)
F3
C
C
Br
F3
3aeA 61% (x = 5)
3afA 87% (x = 5)
3agA 84% (x = 10)
N
N
3ahA 79% (x = 10)
3aiA 99% (x = 10)
3ajA 52% (x = 40)
S
S
Cl
Cl
NH2 Cl
Cl
3mB 83% (x = 5)
3mE 25% (x = 50)
3mC 97% (x = 5)
3mF 99% (x = 10)
3mD 49% (x = 50)
Cl
Cl
Si
N
3mG 82% (x = 10)
OH
OH
Cl
Cl
Cl
7
Cl
4
3mH 73% (x = 20)
3mI 94% (x = 50)
3mJ 81% (x = 20)
3mK 50% (x = 50)
a
Reaction conditions: 1 (0.5 mmol), 2 (1.1 equiv, 0.55 mmol),
Pd(OAc)2 (2.3–50 mol ppm), K2CO3 (3.0 equiv, 1.5 mmol), anhyd
EtOH (2 mL), 80 °C, 24 h, isolated yield.
The reaction of 1-chloro-4-iodobenzene (1m) with a variety of
terminal alkynes 2 was next examined. The reaction with (4-
Next, we applied our catalytic system to the dialkynylation of
diiodobenzenes
4 (Scheme 2). The reaction of 1,4-
ethynylphenyl)amine
(2B)
gave
{4-[(4-
diiodobenzene (4a) with ethynylbenzene (2A) in the presence
of 40 mol ppm palladium acetate and potassium carbonate in
anhydrous ethanol gave 1,4-bis(phenylethynyl)benzene (5aA)
in 71% yield. Similarly, 1,2-diiodobenzene (4b) and 1,3-
chlorophenyl)ethynyl]phenyl}amine (3mB) in 83% yield. The
catalytic system could also be applied in the reactions of
several ethynylhetarenes. The reaction of 1m with 3-
ethynylthiophene (2C) proceeded efficiently in the presence of
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Page 4 of 18
diiodobenzene (4c) also participated in the reaction to afford
1,2-bis(ethynylphenyl)benzene (5bA) and 1,3-
bis(ethynylphenyl)benzene (5cA) in yields of 61 and 79%,
respectively. 3,3'-[1,3-Phenylenebis(ethyne-2,1-
diyl)]dipyridine (5cE), which has been used as a ligand for the
formation of metallomacrocyles,19 was obtained in 69% yield
by the reaction of 4c with 3-ethynylbenzene (2E) in the
presence of 100 mol ppm palladium acetate.
is an induction period in this reaction and that palladium
acetate is a precursor of the actual catalytic species. We also
1
2
3
4
5
6
7
8
examined the reaction mixture by transmission electron
microscopy (TEM) (Figure 3), where a variation in size of
palladium nanoparticles was observed. After heating of the
standard mixture of palladium acetate, 1a, 2A, and potassium
carbonate in ethanol at 80 °C for 2 h (0% conversion), TEM
showed the generation of nanoparticles of palldium of average
diameter 2.0 ± 0.7 nm (Figure 3a). In contrast,when the
reaction time was prolonged to 4 hours (42% conversion),
larger nanoparticles (average diameter 4.4 ± 1.0 nm) were
generated (Figure 3b). The particle size gradually decreased
with increasing conversion. When the reaction time was 8
hours, the conversion was 91% and the size of the palladium
nanoparticles was 3.2 ± 0.8 nm (Figure 3c). After completion of
the reaction, the palladium nanoparticles were of a similar size
(2.2 ± 0.5 nm; Figure 3d) to those generated during the
induction period (2.0 ± 0.7 nm; Figure 3a). These results
suggest that palladium species (monomeric palladium and/or
fine palladium clusters) are liberated from the palladium
nanoparticles during the reaction proceeded (Scheme 4).
9
Scheme 2. Dialkynylation of Diiodobenzenes
Ethynylbenzene (2A) Or 3-Ethynylpyridine (2E)a
4
with
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50
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60
Pd(OAc)2 (x mol ppm)
I
+
Y
K2CO3 (6 equiv)
EtOH, 80 ºC, 24 h
Y
I
4
2A 2E
or
5
(2.2 equiv)
Y
5aA
5bA
61% (x = 40)
71% (x = 40)
We also performed a poisoning experiment (Scheme 5).22 Four
hours after the start of the reaction (24% conversion), mercury
was added to the mixture, completely stopping the reaction.
The above experimental results show that a monomeric
palladium(0) species and/or fine palladium(0) clusters
generated from palladium acetate might be an actual
catalytically active species in this reaction.23
N
N
5cA
5cE
69% (x = 100)
79% (x = 40)
a
Reaction conditions: 4 (0.5 mmol), 2 (2.2 equiv, 1.1 mmol),
Pd(OAc)2 (40–100 mol ppm), K2CO3 (6.0 equiv, 3.0 mmol), anhyd
EtOH (2 mL), 80 °C, 24 h. Isolated yields are reported.
Derivatization of an internal alkyne product was also tested
(Scheme
3).
Cyclization
of
1-methoxy-2-
(phenylethynyl)benzene (3wA) with iodine in water afforded
3-iodo-2-phenylbenzofuran (6) in 84% yield.20 The iodo
compound 6 reacted further with 2A under the coupling
conditions in the presence of a 40 mol ppm of palladium
acetate to give 2-phenyl-3-(phenylethynyl)benzofuran (7), also
in 84% yield. 21
Scheme 3. Synthesis of a Disubstituted Benzofuran 7a
2A
(1.1 equiv)
I
I2 (1.1 equiv)
Pd(OAc)2 (50 mol ppm)
H2O, 24 ºC, 3 h
K2CO3 (3.0 equiv)
EtOH, 80 ºC, 24 h
O
O
OMe
3wA
6
7
(84%)
(84%)
a
Reaction conditions: 4 (0.5 mmol), 2 (2.2 equiv, 1.1 mmol),
Pd(OAc)2 (40–100 mol ppm), K2CO3 (6.0 equiv, 3.0 mmol), anhyd
EtOH (2 mL), 80 °C, 24 h. Isolated yields are reported.
Figure 2. Analysis of the rate of reaction of 4-iodotoluene (1a) with
ethynylbenzene (2A) in the presence of palladium acetate.
Reaction conditions: 1a (0.5 mmol), 2A (0.75 mmol), Pd(OAc)2 (2.5
× 10–6 mmol), K2CO3 (1.5 mmol), anhyd EtOH (2 mL), 80 °C.
To understand the nature of the catalytically active species in
our reaction, we performed the reaction-rate analysis as well
as TEM analysis in a snapshot manner for the reaction of 4-
iodotoluene (1a) with ethynylbenzene (2A) (Figures 2 and 3,
and also see Figure S1 in the Supporting Information)). When
palladium acetate was added into an ethanol solution of 1a
and 2A under the standard reaction conditions, the reaction
did not proceed during the initial 2 hours, showing that there
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ACS Catalysis
Scheme 4. Schematic Proposal for Variation in Size of Pd
1
2
Nanoparticles during the Reaction.
3
4
5
6
7
8
9
(a) TEM-2A: After 2 h,  = 2.0 ± 0.7 nm
(b) TEM-2B: After 4 h,  = 4.4 ± 1.0 nm
(c) TEM-2C: After 8 h,  = 3.2 ± 0.8 nm
(d) TEM-2D: After 10 h,  = 2.2 ± 0.5 nm
10
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Scheme 5. Mercury-Amalgamation Test
Pd(OAc)2 (5.0 mol ppm Pd)
Hg (1 drop)
80 ºC, 8 h
1a
+
2A
3aA
3aA
K2CO3 (3.0 equiv)
EtOH, 80 ºC, 4 h
(1.1 equiv)
24% conv.
24% conv.
CONCLUSION
In summary, we found that palladium acetate is a good catalyst
precursor for the arylation of terminal alkynes by aryl iodides.
The reaction of aryl iodides with terminal alkynes was carried
out in the presence of 2.3–100 mol ppm of palladium acetate
and potassium carbonate in ethanol at 80 °C to give the
corresponding internal alkynes in good to excellent yields.
Reaction-rate analysis, TEM analysis, and
a mercury-
amalgamation experiment suggested that monomeric
palladium(0) and/or fine palladium(0) clusters might be the
actual catalytically active species in this reaction.
ASSOCIATED CONTENT
Supporting Information
General experimental methods, TEM images, and NMR and Mass
data of products (PDF). This material is available free of charge on
the ACS Publication website at DOI: XXXXXXXXXXXXXX.
AUTHOR INFORMATION
Corresponding Author
E-meil: uo@ims.ac.jp
ORCID
Figure 3. TEM images and size distribution histograms in the
reaction shown in Figure 2.
Yasuhiro Uozumi: 0000-0001-6805-3422
NOTE
The authors declare no competing financial interest.
Author Contributions
The manuscript was written through contributions of all authors.
ACKNOWLEDGMENT
This research project was supported by the JST-ACCEL program
(JPMJAC1401). We appreciate funding from the JSPS Grant-in-Aid
for Young Scientists (B) No. 17K14524.
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S.; Wu, W.; Jiang, H. Recent Advances in Pd-Catalyzed Cross-
Coupling Reaction in Ionic Liquids. Eur. J. Org. Chem. 2018,
1284–1306.
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Scheme 1
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Pd(OAc)2 (x mol ppm)
I
R2
R2
+
R1
R1
K2CO3 (3 equiv)
EtOH, 80 ˚C, 24 h
10
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2 (1.1 equiv)
1
3
R
R
R
3vA R = Me, 99% (x = 2.3)
3oA R = Me, 99% (x = 2.3)
3pA R = OMe, 88% (x = 10)
3qA R = CF3, 99% (x = 2.3)
3rA R = NO2, 90% (x = 10)
3sA R = COMe, 73% (x = 5)
3tA R = Cl, 99% (x = 2.3)
3uA R = Br, 70% (x = 10)
3aA R = Me, 93% (x = 2.3)
3bA R = H, 97% (x = 2.3)
3cA R = OMe, 99% (x = 10)
3dA R = t-Bu, 98% (x = 5)
3eA R = Ph, 88% (x = 5)
3fA R = CF3, 97% (x = 2.3)
3gA R = COMe, 88% (x = 2.3)
3hA R = CO2Et, 46% (x = 5)
3iA R = CN, 76% (x = 5)
3jA R = NO2, 84% (x = 10)
3kA R = CH2OH, 90% (x = 5)
3lA R = F, 90% (x = 5)
3wA R = OMe, 71% (x = 10)
3xA R = i-Pr, 91% (x = 10)
3yA R = Ph, 72% (x = 10)
3zA R = F, 88% (x = 5)
3aaA R = Cl, 99% (x = 10)
3abA R = Br, 63% (x = 5)
OMe
OMe
3mA R = Cl, 92% (x = 2.3)
3nA R = Br, 61% (x = 5)
3acA 71% (x = 10)
3adA 45% (x = 10)
F3C
Br
F3C
3aeA 61% (x = 5)
3afA 87% (x = 5)
3agA 84% (x = 10)
N
N
3ahA 79% (x = 10)
3aiA 99% (x = 10)
3ajA 52% (x = 40)
S
S
Cl
Cl
NH2 Cl
Cl
3mB 83% (x = 5)
3mE 25% (x = 50)
3mC 97% (x = 5)
3mD 49% (x = 50)
Cl
Cl
Si
N
3mF 99% (x = 10)
3mG 82% (x = 10)
OH
OH
Cl
Cl
Cl
Cl
7
4
3mH 73% (x = 20)
3mI 94% (x = 50)
3mJ 81% (x = 20)
3mK 50% (x = 50)
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Pd(OAc)2 (x mol ppm)
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I
+
Y
K2CO3 (6 equiv)
EtOH, 80 ˚C, 24 h
Y
I
Y
4
2A or 2E (2.2 equiv)
5aA 71% (x = 40)
5cA 79% (x = 40)
5
5bA 61% (x = 40)
N
N
5cE 69% (x = 100)
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Scheme 3
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I
2A (1.1 equiv)
Pd(OAc)2 (50 mol ppm)
I2 (1.1 equiv)
H2O, 24 ˚C, 3 h
K2CO3 (3.0 equiv)
EtOH, 80 ˚C, 24 h
O
O
OMe
3wA
6 (84%)
7 (84%)
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ACS Catalysis
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Scheme 4
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9
liberate
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via
monomeric Pd
aggregate
Scheme 5
Pd(OAc)2 (5.0 mol ppm Pd)
Hg (1 drop)
80 ˚C, 8 h
+
1a
2A
3aA
3aA
K2CO3 (3.0 equiv)
EtOH, 80 ˚C, 4 h
(1.1 equiv)
24% conv.
24% conv.
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Figure 1 (a) (b)
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(b)
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ACS Catalysis
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Figure 1 (c) (d)
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(c)
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(d)
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Figure 2
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TEM-2D
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TEM-2C
TEM-2B
TEM-2A
induction period
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ACS Catalysis
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Figure 3 (a) (b)
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(b)
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Figure 3 (c) (d)
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(d)
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